1. Field of the Invention
The present invention concerns the preparation of liposomal formulations containing Temoporfin or other hydrophobic, photosensitizers and their use in therapy, particularly using intravenous injection.
2. Information Disclosure Statement
Liposomes are artificial vesicles composed of concentric lipid bilayers separated by water-compartments and have been extensively investigated as drug delivery vehicles. Due to their structure, chemical composition and colloidal size, all of which can be well controlled by preparation methods, liposomes exhibit several properties which may be useful in various applications. The most important properties are colloidal size, i.e. rather uniform particle size distributions in the range from 20 nm to 10 μm, and special membrane and surface characteristics.
Liposomes are used as carriers for drugs and antigens because they can serve several different purposes (Storm & Crommelin, Pharmaceutical Science & Technology Today, 1, 19-31 1998). Liposome encapsulated drugs are inaccessible to metabolizing enzymes. Conversely, body components (such as erythrocytes or tissues at the injection site) are not directly exposed to the full dose of the drug. The Duration of drug action can be prolonged by liposomes because of a slower release of the drug in the body. Liposomes possessing a direction potential, that means, targeting options change the distribution of the drug over the body. Cells use endocytosis or phagocytosis mechanism to take up liposomes into the cytosol. Furthermore liposomes can protect a drug against degradation (e.g. metabolic degradation). Although sometimes successful, liposomes have limitations. Liposomes not only deliver drugs to diseased tissue, but also rapidly enter the liver, spleen, kidneys and Reticuloendothelial Systems, and leak drugs while in circulation (Harris & Chess, Nature, March 2003, 2, 214-221).
Photodynamic therapy (PDT) is a promising new technique being explored for use in a variety of medical applications and is known as a well-recognized treatment for the destruction of tumors (“Pharmaceutical development and medical applications of porphyrin-type macrocycles”, T. D. Mody, J. Porphyrins Phthalocyanines, 4, 362-367 2000). Another possible application of PDT is the treatment of infectious diseases due to pathogenic micro organisms.
A constant problem in the treatment of infectious disease is the lack of specificity of the agents used for the treatment of disease, which results in the patient gaining a new set of maladies from the therapy. Secondly, micro organisms can adapt to negate the effect of most chemically designed antimicrobials creating resistant strains, which require ever more active ingredients to stop their activity.
The use of PDT for the treatment of various types of disease has been limited due to the inherent features of photosensitizers (PS). These have included their high cost, extended retention in the host organism, substantial skin photo toxicity, low solubility in physiological solutions (which also reduces its usefulness for intravascular administration as it can provoke thromboembolic accidents), and low targeting effectiveness. These disadvantages, particularly of PS in the prior art, had led to the administration of very high doses of a photosensitizer, which dramatically increase the possibility of accumulation of the photosensitizer in non-damaged tissues and the accompanying risk of affecting non-damaged sites.
Efforts to reduce cost and to decrease background toxicity have been underway but are unrelated to the developments of the present invention. Work to improve solubility in physiological solutions, effects of skin photo toxicity, retention in host organism and to a lesser extent targeting effectiveness are the areas where the present invention provides new and non-obvious improvements on the use of PDT to treat various hyperplasia and related diseases.
Desai et al. (U.S. Pat. No. 6,074,666) and a recent publication, US 2005/0107329 also by Desai et al. describe the preparation and use of liposomal formulations incorporating porphyrin photosensitizers, particularly hydro-benzoporphyrins, a disaccharide or polysaccharide and one or more phospholipids. These phospholipids are quite general, but generally included at least one ‘natural’ phospholipid, e.g. from eggs or soy. The preferred porphyrin photosensitizers are mono-substituted with a benzo-ring connected to one of the four pyrryl rings in the porphyrin. The use of disaccharides or polysaccharides is required along with one or more phospholipids used to make the liposomes. Using the broad range of permitted phospholipids and the di- and poly-saccharides with materials like chlorins, bacteriochlorins, and especially tetra-substituted derivatives of these does not necessarily yield stable liposomes capable of freeze drying and reconstitution.
Since the application of photodynamic therapy in the treatment of cancer and other diseases is increasing rapidly, there is also a bigger demand for new photosensitizer formulations. These new photosensitizer formulations need to be stable, easy to manufacture and to handle.